The mechanisms underlying the failure of B-NHL cancer patients to respond to treatment with rituximab, alone or in combination with chemotherapy, are not known. In efforts to address this issue, we have generated rituximab-resistant clones of the AIDS NHL cell line, (2F7RR). Recent findings have demonstrated that treatment of the wild type (wt) 2F7 with rituximab sensitized the tumor cells to various chemotherapeutic drug-induced apoptosis. Chemosensitization was the result of rituximab-mediated inhibition of the p38 MAPK signaling pathway and the selective inhibition of the anti-apoptotic Bcl-2 gene product (

Vega et. al.,
Oncogene
23
:
4993
,
2004
). Analysis of one clone, 2F7RR1, revealed that the cells have diminished surface CD20 expression and failed to respond to CDC and to apoptosis following cross-linking. In addition, the cells were resistant to rituximab-mediated chemosensitization. In contrast to wt2F7, molecular analysis of the 2F7RR1 clone revealed that rituximab failed to inhibit p-Lyn, p38-MAPK, BclXL, and Bcl-2. In addition, rituximab failed to inhibit the transcription factors NF-κB, YY1, SP-1, and STAT3. Noteworthy, 2F7RR1 exhibited higher resistance to drug-induced apoptosis compared to wt2F7 and showed overexpression of Bcl-2. Previous findings with the wt2F7 demonstrated that Bcl-2 was responsible for chemoresistance. Accordingly, we examined whether inhibition of Bcl-2 in 2F7RR1 can reverse chemoresistance. Since Bcl-2 is under the transcriptional regulation of NF-κB, we examined the effect of the NF-κB inhibitors Bortezomib and DHMEQ (DHMEQ was a kind gift from Dr.K. Umezawa Keio University, Japan) (Kikuchi, et al., Cancer Review, 2003, 63:107). The findings revealed that treatment of 2F7RR1 with these inhibitors resulted in the reversal of resistance to a number of chemotherapeutic drugs (examples: taxol, vincristine, ADR, CDDP, VP16, etc.). The chemo-sensitization by Bortezomib and DHMEQ was equivalent and the combination treatment of each of these inhibitors with the drug was synergistic. These studies present evidence that rituximab and drug-resistant tumor cells may be sensitized to chemotherapeutic drug-induced apoptosis via inhibition of NF-κB or Bcl-2. These findings also suggest that Bortezomib and DHMEQ may be clinically relevant in the treatment of rituximab and drug-resistant AIDS-B-NHL.

Topics:
acquired immunodeficiency syndrome, apoptosis, bortezomib, clone cells, rituximab, cancer, chemotherapy regimen, mitogen-activated protein kinase p38, tumor cells, antineoplastic agents

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2005, The American Society of Hematology
2005
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